Fasting hyperglycemia in patients with poorly controlled type II diabetes mellitus is closely associated with increased rates of glucose production which in turn can be ascribed to increased rates of gluconeogenesis. A number of studies have demonstrated that elevated glucagon level is partially responsible for the increased hepatic glucose production in patients with type 2 diabetes.
Glucagon is a 29-amino-acid hormone in the pancreatic alpha cells, which plays a major counter-regulatory role for insulin action. During fasting, glucagon secretion increases in response to the low circulating glucose levels. Increased glucagon secretion stimulates glucose production by promoting hepatic gluconeogenesis and glycogenolysis. In addition, glucagon reduces glycogen synthesis in the liver. Clinically, glucagon is administered to patients who are at risk for significant hypoglycemia. Conversely, inhibition of the glucagon pathway may offer a strategy for the treatment of type II diabetes.
The biological effects of glucagon are mediated through its binding to a specific receptor on cell surface, glucagon receptor, and subsequent activation of the signaling pathway. The glucagon receptor belongs to the family B G-protein coupled receptor (GPCR). It is predominantly expressed in liver and kidney, which reflects its primary role as a regulator of glucose output and gluconeogenesis in these tissues. The activation of glucagon receptor in the liver stimulates adenylyl cyclase activity and phosphoinositol turnover, resulting in increased expression of several key gluconeogenic enzymes.
Considering the key role of glucagon in control of hyperglycemia, strategy for inhibiting glucagon activation pathway can provide a therapeutic means to treat type II diabetes.